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PoD - E4 > Anti-pyretics, Anti-inflammatory, and Analgesics > Flashcards

Anti-pyretics, Anti-inflammatory, and Analgesics Flashcards

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1
Q

Eicosanoids

A

Members of a family of oxygenated products of polyunsaturated fatty acids. Includes:

  • Prostaglandins (PGs)
  • Thromboxanes (TBs)
  • Leukotrienes (LTs)
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2
Q

Prostaglandins include

A

PGD2, PGF2alpha, PGI2

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3
Q

Thromboxanes include

A

TXA2

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4
Q

Leukotrienes include

A

LTC4, LTD4, LTE4

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5
Q

Eicosanoid fatty acid precursors

A
  • Dihomo-gamma- linoleic acid
  • Arachidonic acid
  • Eicosapentaenoic acid

The nature of the precursor PUFA affects the function of the eicosanoid synthesized

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6
Q

Arachidonic acid

A
  • Most abundant and most important precursor of eicosanoids
  • Synthesized from linoleic acid (essential fatty acid)
  • Arachidonic acid = eicosa tetraenoic (5, 8, 11, 14) acid
  • 20 carbons, 4 unsaturated bonds
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7
Q

Prostanoids refers to

A

Products of cyclooxygenase:

  • Prostacyclins
  • Prostaglandins
  • Thromboxanes
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8
Q

COX-1

A
  • Constitutive form
  • Found in endothelial cells, stomach and kidney
  • House keeping functions (always present), widely distributed: ↑ stomach mucus → protection of stomach mucosa from HCl
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9
Q

COX-2

A
  • Inducible form
  • Elevated by inflammation and by cytokines
  • Constitutively expressed in brain and kidney
  • Immediate early response gene product in inflammatory/ immune cells (inflammation in rheumatoid arthritis)
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10
Q

Prostanoids - Mechanism of Action

A
  • Act locally (short half-lives) - paracrine or autocrine
  • Have cell surface receptors (GPCRs)
  • Activate G proteins ( ↓ intracellular calcium) or phosphatidyl inositol metabolism (↑ intracellular calcium)
  • Major effects are on 4 types of smooth m.: vascular, gastrointestinal, airway and reproductive
  • Other targets: platelets, monocytes, kidneys, CNS, sensory nerve endings, endocrine organs, and the eye (this may involved smooth m.)
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11
Q

Prostacyclin (PGI2) - Vascular Action

A
  • Synthesized by both smooth m. cells and endothelial cells (major contributor - COX2)
  • Relaxes vascular smooth m.
  • POWERFUL VASODILATOR: ↑ cAMP, ↓ intracellular calcium
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12
Q

Prostacyclin (PGI2) - Airway Action

A
  • POWERFUL BRONCHODILATOR (most potent)
  • Used clinically to treat pulmonary (induced by hypoxia) and portopulmonary hypertension

Portopulmonary = portal + pulmonary hypertension

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13
Q

Prostacyclin (PGI2) - GI Action

A
  • Inhibits gastric acid secretion

- Increased mucus secretion

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14
Q

Prostacyclin (PGI2) - Renal Action

A
  • Increases GFR and renal blood flow
  • Increases water and sodium excretion
  • Stimulates renin release (cortex)
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15
Q

Prostacyclin (PGI2) - Reproductive Action

A
  • Relaxes uterine muscle
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16
Q

Prostacyclin (PGI2) - Pain Action

A
  • Induces pain by lowering threshold of nociceptors
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17
Q

Prostacyclin (PGI2) - Receptors

A
  • IP (Gs - cAMP)
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18
Q

Prostaglandin (PGE2) - Vascular Action

A

Vasodilator

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19
Q

Prostaglandin (PGE2) - Platelet Action

A

- [High]: inhibits platelet aggregation

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20
Q

Prostaglandin (PGE2) - Airway Action

A
  • Relaxes respiratory smooth m.

- POWER BRONCHODILATOR

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21
Q

Prostaglandin (PGE2) - GI Action

A
  • Inhibits gastric acid secretion

- Increases stomach mucus secretion

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22
Q

Prostaglandin (PGE2) - Renal Action

A
  • Increases GFR
  • Increases renal blood flow
  • Increases water and sodium excretion
  • Stimulates renin release (cortex)
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23
Q

Prostaglandin (PGE2) - Reproductive Action

A

Dysmenorrhea = painful menstruation

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24
Q

Prostaglandin (PGE2) - Pain Action

A
  • Induces pain by lowering the threshold of nociceptors
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25
Prostaglandin (PGE2) - Fever Action
- Induces fever in hypothalamus (DIRECT PYROGEN) | - Cytokines can stimulate PGE2
26
Prostaglandin (PGE2) - Receptor
EP1 - EP4 (Gs, Gq)
27
Thromboxane (TXA2) - Synthesis
Synthesized by platelets, lung and kidney
28
Thromboxane (TXA2) - Vascular Action
- POTENT VASOCONSTRICTOR - SMC mitogen SMC = smooth muscle cell
29
Thromboxane (TXA2) - Platelet Action
- MAJOR PRODUCT OF PLATELET COX1 - STIMULATES PLATELET AGGREGATION - Also acts as an amplification signal for other more potent agonists such as thrombin and ADP
30
Thromboxane (TXA2) - Airway Action
- Constricts airway smooth m.
31
Thromboxane (TXA2) - Renal Action
- Intra-renal vasoconstriction (perhaps an ADH-like effects) resulting in decline in renal function - Normal kidney synthesizes very little TXA2
32
Thromboxane (TXA2) - Reproductive Action
- Uterine muscle contraction
33
Thromboxane (TXA2) - Receptor
TP (PLC)
34
Prostaglandin F2alpha (PGF2alpha) - Vascular Action
- Vasoconstrictor
35
Prostaglandin F2alpha (PGF2alpha) - Airway Action
- Contracts airway smooth m.
36
Prostaglandin F2alpha (PGF2alpha) - Reproductive Action
- CONTRACTS UTERINE MUSCLE (similar to PGE2 can terminate pregnancy) - In combination with oxytocin can induce labor, causes dysmenorrhea
37
Prostaglandin F2alpha (PGF2alpha) - Eye Action
- Decreases intraocular pressure - Used to treat glaucoma - a condition associated with a loss of COX2 expression in the pigmented epithelium of the ciliary body
38
Misoprostol
- PGE1 analog - INHIBITS GASTRIC ACID SECRETION (increasing production of gastric mucus and mucosal secretion of bicarbonate) - Adjunct to NSAID therapy to reduce ulcer formation in high risk patients (i.e. elderly and patients with concomitant debilitating disease) - Should be taken for the duration of the NSAID therapy - Contraindication in pregnancy (may induce uterine contractions and induce labor)
39
Latanoprost
- PGF2alpha analog - Ophthalmic preparation - Used for OPEN ANGLE GLAUCOMA to LOWER INTRAOCULAR PRESSURE (increases aqueous humor outflow)
40
Alprostadil
- PGE1 analog - TEMPORARILY MAINTAINS PATENT DUCTUS ARTERIOSUS in newborns until surgery can be done - Administer by IV infusion - Increase pulmonary blood flow (vasodilator), IMPROVES BLOOD OXYGENATION - Other uses: erectile dysfunction
41
Leukotriene
- Products of lipoxygenases | - Arachidonic acid converted by lipoxygenase pathway to leukotrienes
42
5-HETE (5-HPETE) and Leukotriene B4 (LTB4)
- Lipoxygenase product - CHEMOTACTIC AGENT for polymorphonuclear leukocytes, eosinophils and monocytes - LTB4 can also produce hyperalgesia - Human colonic epithelial cells synthesize LTB4 - Patients with IBD contains substantial amounts of LTB4 ``` Hyperalgesia = abnormally heightened sensitivity to pain IBD = inflammatory bowel disease ```
43
Cysteinyl Leukotrienes (LTC4/C4, LTD4/D4, LTE4/E4)
- Chemoattractant for eosinophils - POTENT BRONCHOCONSTRICTORS (act principally on airway smooth muscle cells) - INCREASE VASCULAR PERMEABILITY (1000x more potent than histamine) - COMPONENTS OF SLOW REACTING SUBSTANCE OF ANAPHYLAXIS (SRS-A) that is secreted in asthma and anaphylaxis
44
4 current approaches to anti-leukotriene drug development
1. Leukotriene receptor antagonists 2. 5-LOX inhibitors 3. Inhibitors of FLAP (5-lipoxygenase activated protein) 4. Phospholipase A2 inhibitor
45
Competitive, Leukotriene D4 receptor antagonists (Cys-LT1)
- Zafirlukast | - Montelukast
46
5-Lipoxygenase inhibitors
- Zileuton
47
Zafirlukast and Montelukast - Mechanism of Action and Uses
- Competitive, reversible LTD4 (cysteinyl leukotriene 1) receptor antagonist - Inhibit the leukotriene mediated effects on bronchoconstriction and vascular permeability - PROPHYLACTIC TREATMENT OF ASTHMA - not used for acute asthmatic attacks, used in children and adults, m > 1 yo, z > 5 yo - Exercise induced bronchoconstriction (m > 15 yo) - Allergic rhinitis - Aspirin sensitivity induced asthma (m only)
48
Zafirlukast - Adverse Effects
- Headache - Pharyngitis - Rare cases of increased liver enzymes
49
Zafirlukast - Drug Interactions
- Inhibits CYP3A4 and CYP2C9 - Numerous drug interactions (i.e. warfarin) - Take on empty stomach (food reduces bioavailability by 40%)
50
Montelukast - Adverse Effects
- Headache
51
Montelukast vs Zafirlukast
- Montelukast - 1x per day - Zafirlukast - 2x per day - Zafirlukast must be taken on empty stomach - Zafirlukast inhibits CYP3A4 and CYP2C9 - Montelukast can be used in children
52
Zileuton - Mechanism of Action
- Inhibitor of 5-lipoxygenase | - Inhibits the synthesis of LTA4, B4, C4, D4, D4 and E4
53
Zileuton - Uses
- Prophylaxis for asthma (>12 yo)
54
Zileuton - Adverse Effects
- Must monitor hepatic function (hepatic transaminase may increase up to 3x of normal) - Cannot be used in those with liver disease
55
Zileuton - Drug interactions
- Increase response: theophylline (blood levels double), warfarin, propranolol - Ergot alkaloids contraindicated - severe vomiting, vasospasms
56
NSAID
- Chemically diverse class of drugs - Most frequently prescribed drugs - Many available OTC - Mechanism of action: inhibits cycloxygenase
57
Non-selective NSAIDs
- Inhibit both COX1 and COX2 Salicylates: - Aspirin (irreversible inhibitor)
58
Traditional NSAIDs
Propionic acid: - Ibuprofen - Naproxen - Oxaprozin Acetic acid: - Indomethacin - Sulindac - Ketoralac - Diclofenac
59
Selective NSAIDs
- COX2 specific inhibitor - Celecoxib - Valdecoxib - Rofecoxib
60
Common therapeutic actions of NSAIDs
- ANTIPYRETICS: inhibit PGE synthesis in the hypothalamus (lowering of an elevated temperature) - ANALGESICS: reduction of mild to moderate pain, pain associated with inflammation - Good ANTI-INFLAMMATORY properties: inhibits prostaglandin synthesis in localized areas
61
Common side effects associated with NSAID
- Increased risk of GI ulcers and pain - Increased risk of bleeding (inhibit platelet aggregation) - Inhibit prostaglandin mediated effects in kidney (sodium and water retention) - Cross sensitivity with aspirin (aspirin sensitivity is a contraindication)
62
Aspirin - Mechanism of Action
- Salicylate - Also called acetyl salicylate - IRREVERSIBLE inhibitor of cyclooxygenase - ACETYLATES the enzyme (ser 530 in COX1, ser 516 in COX2)
63
Aspirin - Uses
- Antipyretic, anti-inflammatory and analgesic agent - Analgesic activity at localized area and in brain but DOES NOT interact with opioid receptor - Therapeutic limitation for arthritis (rheumatoid and osteoarthritis) - therapeutic dose approaches side effect dose
64
Aspirin - Effect on Platelets
- IRREVERSIBLY INHIBITS platelet COX - Low does can irreversibly inhibit TXA2 production in platelets (effect lasts 8-10 days - the life of the platelet) - This prolongs bleeding time
65
Aspirin - Clinical Uses
- Decreases incidence transient ischemic attacks, unstable angina, coronary artery thrombosis with MI and thrombosis after CABG - Reduces risk of preeclampsia in women (administered late 1st trimester for women with history and after 34 weeks for women who show high risk) - Long term use may lower incidence of colon cancer
66
Salicylate preparations
- Aspirin (acetyl salicylate): buffered, enteric coated effervescent (very high sodium level) - Topical salicylate: methyl salicylate (oil of wintergreen), choline magnesium salicylate - Mesalamine (5-aminosalicylic acid, Asacol): treatment of inflammatory bowel disease
67
Aspirin - Side Effects
- GI PAIN, BLEEDING AND ULCERS - Variable urate excretion (decreased 5 g) - Reye's syndrome (do not give to children with influenza or varicella) - SALICYLISM: mild intoxication with aspirin and salicylates; commonly experienced when daily does exceeds 4 g; characterized by TINNITIS (high frequency hearing loss), headache, nausea, dimness of vision; symptoms are usually reversible within 2-3 days after withdrawal of drug
68
Propionic acid derivatives
- Ibuprofen | - Naproxen
69
Heteroarylacetic acid derivatives
- Ketorolac
70
Phenylacetic acid derivatives
- Diclofenac
71
Indole derivatives
- Indomethacin
72
Selective COX2 inhibitors
- Coxibs
73
Propionic acid and Arylacetic acid derivative - Uses
- Competitive, REVERSIBLE active-site inhibitors of COX1 and COX2 Uses: - Mild to moderate pain - Anti-pyretic - Symptoms of rheumatoid and osteoarthritis - Less GI ulcers and problems than aspirin
74
Ibuprofen - Uses
- Fever in children - Dysmenorrhea - Acute migraine attacks - Rheumatoid and osteoarthritis
75
Naproxen - Uses
- Greater inflammatory action, can be used the same as ibuprofen - Osteoarthritis, rheumatoid - Acute gout - Tendonitis (shoulder) - Ankylosing spondylitis
76
Naproxen - Adverse Effects
- Clearance is reduced in liver disease - Increased risk of stroke/heart attack with prolonged use - ACE inhibitors - NSAIDs seem to diminish the anti-hypertensive effects of ACE inhibitors (due to inhibitor of vasodilator and natriuretic PGs) - Antacids and Sucralfate (Al and Mg containing agents) - delays absorption
77
Ketorolac - Uses
- Excellent analgesic action - NSAID used for postoperative pain (moderate to severe) - Analgesia, comparable to morphine (short term alternative) - Administer IM, IV, oral - Advantage to morphine - not habit forming - Given 5 days max - Analgesic > anti-inflammatory activity - Inhibits platelet aggregation
78
Ketorolac - Adverse Effects
- GI bleeding - Bleeding (inhibits platelet aggregation) - Hepatic (monitor AST/ALT levels) - Lower dose in patients under 110 lbs or over 65 yo or ELEVATED CREATININE
79
Ketorolac - Contraindications
- History of peptic ulcer or presence of GI bleeding - Must stop before surgery - CONCURRENT USE WITH ASPIRIN OR NSAID - Use in renal disease - Combined with probenecid (used in treatment of gout) - Active bleeding (GI, cerebrovascular) - During labor/delivery or during lactation
80
Diclofenac - Uses
- Rheumatoid, osteoarthritis, and ankylosing spondylitis - Primary dysmenorrhea (diclofenac potassium only) - Ophthalmic: postoperative pain and inflammation following cataract surgery - Arthrotec: DICLOFENAC + MISOPROSTOL used in patients with risk of gastric or duodenal ulcers (contraindicated in pregnancy) - Low dosage: mild to moderate acute pain
81
Diclofenac - Adverse Effects
- GI pain, nausea cramps, diarrhea - Modest elevation of ALT - Dizziness - Headache - ARTHROTEC CONTRAINDICATED DURING PREGNANCY - METABOLIZED BY CYP2C9
82
Indomethacin - Uses
- Oral: acute gouty arthritis, rheumatoid (moderate to severe), osteoarthritis (moderate to severe), tendinitis, ankylosing spondylitis - IV: nonsurgical repair of patent ductus arterioles (close PDA)
83
Indomethacin - Side Effects
- GI pain (take with food) - Severe frontal headache - Displacement of bilirubin from albumin - Decreased urine output - Contraindications: hyperbilirubinemia, renal failure
84
Celecoxib - Uses
- Rheumatoid and osteoarthritis - Akylosing spondylitis - Primary dysmenorrhea
85
Celecoxib - Interactions
- Metabolized by P450 CYP2C9 | - Monitor dose carefully when given with FLUCONAZOLE (inhibits CYP2C9)
86
Celecoxib - Adverse Effects
- GI pain | - Nausea
87
NSAIDs and Pregnancy
- Inhibit uterine motility (PGE and PGF) - Induce bleeding in last trimester - Premature closing of ductus arteriosus
88
Prostaglandin with high risk of acute renal failure
Indomethacin
89
Water and sodium retention mechanism - PGI2 and PGE2
- Increase GFR - Increase renal blood flow - PGE2: inhibits Cl- reabsorption in thick ascending limb of the loop of Henle
90
Water and sodium retention mechanism - NSAIDs
- Lower PGI2, PGE2, TXA2 - Resulting in decreased renal blood flow and glomerular filtration rate, increase tubular reabsorption of water, Cl, and Na
91
Hyperkalemia likely to occur with NSAID use when
- Used in elderly, diabetics and other situations of diminished renal function - Individuals should monitor weight in order to assess whether water retention is occurring Combination with: - Propranolol (less renin and aldosterone) - Potassium sparing diuretics - ACE inhibitors (decreases kinins which decrease renin release)
92
Hyperkalemia and water retention mechanism - PGI2 and PGE2
- Stimulate renin release | - PGE2: inhibits the effect of anti-diuretic hormone (ADH) on collecting tubules
93
Hyperkalemia and water retention mechanism - NSAIDs
- Will lower renal PG levels - Result in enhanced ability of ADH to increase permeability of collecting tubules to water (water retention) - Decrease K secretion (K+ retention)
94
Acetaminophen - Uses
- Alternative drug in people that are aspirin sensitive - Active metabolite of phenacetin - Excellent antipyretic and analgesic (mild to moderate pain, osteoarthritis) activity comparable to aspirin - Weak anti-inflammatory agent - DOES NOT alter platelet function - Less GI upset
95
Acetaminophen - Mechanism of Action
- Weak inhibitor of cycle-oxygenase (COX1 and COX2) - Mechanism - COX3 inhibitor????? - Activates cannabanoid receptor
96
Acetaminophen - Interactions
- Ethanol
97
Acetaminophen - Adverse Effects
- Hepatic toxicity (acute) - #1 cause of drug induced liver failure in US - Renal toxicity (chronic)
98
Gold Salts
- Auranofin | - Gold sodium thiomalate
99
Auranofin and Gold sodium thiomalate - Uses
- Used for ACTIVE rheumatoid arthritis that are not responding to NSAIDs - Not first line due to side effects - GST: administer IM, used for more aggressive treatment
100
Auranofin and Gold sodium thiomalate - Mechanism of Action
- Inhibit function and maturation of T cell - Decreased level of rheumatoid factor (IgM) - Inhibits phagocytosis by macrophages
101
Auranofin and Gold sodium thiomalate - Adverse Effects
- Develop rash and/or skin lesions of mucous membrane - CHRYSIASIS: gold deposit in skin, gray color esp. upon sun exposure - PROTEINURIA AND GLOMERULONEPHRITIS
102
Gold Sodium Thiomalate - Adverse effects
- Greater risk of chrysalis and mucosal lesions - Anemia and thrombocytopenia - Anaphylactic reaction to injection - CONTRAINDICATIONS: renal disease, lupus, eczema, gold sensitivity
103
What is arachidonic acid cleaved by
Phospholipase A2 and C
104
Prostaglandin synthetase is a combination of
Cyclooxygenase + peroxide
105
Enzymes that use prostaglandin as a substrate
- Prostacyclin synthase - Thromboxane synthase - Endoperoxide isomerase - Endoperoxide reductase
106
Kind of pyrogen PGE2 is in hypothalamus
- DIRECT - PMNs release cytokines (IL-1) which cross into the hypothalamus - IL-1 increases PGE2 levels
107
What is thromboxane a major product of
Platelet COX1

PoD - E4 (5 decks)

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